Project Summary Development of therapies to treat the motor and cognitive deficits resulting from cerebellar stroke is hindered by our current lack of mouse models to perform mechanistic translational studies. The current proposal represents an important step forward, as we describe a new reproducible animal model of cerebellar stroke that will be used to characterize the functional consequences of cerebellar ischemic stroke and begin to develop strategies to improve functional outcomes. The objective of this proposal is to take advantage of our novel mouse model of cerebellar stroke to elucidate network alterations that result from cerebellar stroke. Our central hypothesis is that cerebellar ischemia causes thalamic hyperexcitability that disrupts sensory transmission and causes excitatory: inhibitory imbalance. This hypothesis was developed on the basis of preliminary data generated in the applicant?s laboratory. The rationale for the proposed research is that understanding network disruptions will allow for the development of novel strategies to improve neurological function independent of neuroprotective strategies that have failed to translate. The hypothesis will be tested by pursuing three specific aims: 1) test if injury size and location correlates with chronic neurological impairments, 2) test if thalamic excitability is altered after cerebellar stroke 3) determine alterations in excitatory and inhibitory synaptic inputs that contribute to hippocampal plasticity deficits. Under the first aim, there is already strong preliminary data to demonstrate motor and cognitive deficits in this novel mouse model of cerebellar stroke. Under the second and third aims, we will use a neurophysiological to interrogate excitability and plasticity changes resulting from cerebellar stroke. Preliminary data indicate that cerebellar ischemic stroke results in thalamic hyperexcitability and impaired hippocampal synaptic plasticity. The approach is innovative as it provides an important tool for performing mechanistic studies and moves away from neuroprotective strategies to focus on restoring neurophysiological function at delayed time points. The proposed research is significant as it is expected to expand understanding of network alterations that contribute to long-lasting deficits. Ultimately, such a knowledge has the potential to inform the development of therapeutic strategies that improve neurological function and quality of life for stroke patients.